Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg)

CA036598

373769 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: eeee2ff5-82c2-479e-abb7-3dbe70976e6b

HGVS expressions

NM_000527.4:c.1774G>A

NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg)

NC_000019.10:g.11116927G>A

CM000681.2:g.11116927G>A

NC_000019.9:g.11227603G>A

CM000681.1:g.11227603G>A

NC_000019.8:g.11088603G>A

NG_009060.1:g.32547G>A

ENST00000558518.6:c.1774G>A

ENST00000252444.9:n.2028G>A

ENST00000455727.6:c.1270G>A

ENST00000535915.5:c.1651G>A

ENST00000545707.5:c.1393G>A

ENST00000557933.5:c.1774G>A

ENST00000558013.5:c.1774G>A

ENST00000558518.5:c.1774G>A

ENST00000559340.1:n.426+715G>A

NM_001195798.1:c.1774G>A

NM_001195799.1:c.1651G>A

NM_001195800.1:c.1270G>A

NM_001195803.1:c.1393G>A

NM_000527.5:c.1774G>A

NM_001195798.2:c.1774G>A

NM_001195799.2:c.1651G>A

NM_001195800.2:c.1270G>A

NM_001195803.2:c.1393G>A

NM_000527.5(LDLR):c.1774G>A (p.Gly592Arg)

Likely Pathogenic

PM2 PM5 PS4_Supporting PP4 PP3

PS2 PS3 PS1 PM6 PM3 PM1 PM4 BA1 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP1 PP2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supportign and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM5 - 1 other missense variant in the same codon, NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP, so PM5 is met. PP3 - REVEL = 0.951. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 index cases with clinical FH criteria (please see PS4 for details), so PP4 is met.

PM2

PopMax MAF = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

PM5

1 other missense variant in the same codon: - NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP so PM5 is met

PS4_Supporting

variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met

PP4

PP3

REVEL = 0.951. It is above 0.75, so PP3 is met

PS2

no de novo occurrence

PS3

There are no functional studies on this variant

PS1

there is no missense variant that leads to the same amino acid change, so not met

PM6

no de novo occurrence

PM3

not identified in cases with other variants

PM1

variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so not met

PM4

variant is missense, so not applicable

BA1

FAF = 0.00002596 (0.003%) in South Asian exomes (gnomAD v2.1.1). It is not above 0.5%, so not met

PVS1

variant is missense and not in initiation codon, so not applicable

BP5

not applicable

BP7

variant is missense, so not applicable

BP2

not identified in cases with other variants

BP3

not applicable

BP4

REVEL = 0.951. It is not below 0.50, so BP4 is not met

BP1

not applicable

BS4

no segregation data

BS3

There are no functional studies on this variant

BS1

FAF = 0.00002596 (0.003%) in South Asian exomes (gnomAD v2.1.1). It is not above 0.5%, so not met

BS2

variant was not tested in normolipidemic individuals, so not met

PP1

no segregation data

PP2

not applicable

Approved on: 2022-08-28

Published on: 2022-08-28

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